G-quadruplexes (GQs) are noncanonical nucleic acid structures that form in guanine-rich sequences of DNA and RNA. GQs are characterized by stacked guanine tetrads that are stabilized by Hoogsteen hydrogen bonding and coordination of monovalent cations, typically K+. DNA GQs are enriched in promoter regions, origins of replication, and telomeres, suggesting important roles in regulation of gene expression and genome maintenance. As such, GQs may serve as drug targets, particularly against various types of cancer, by modulating GQ folding or interactions with proteins. GQ-specific drug design requires an atomistic understanding of their dynamics, with a particular emphasis on ion interactions, which are crucial for stability. To date, molecular dynamics (MD) simulations have suffered from inaccuracies in representing ion-GQ and ion-ion interactions, due primarily to a lack of induced dipole interactions. We have performed a series of polarizable simulations on structurally diverse DNA GQs, including unbiased MD and metadynamics approaches. Our simulations revealed cooperative polarization of guanine base dipoles in the GQ tetrad core, as well as ion binding to outer faces of GQ tetrads, which impacts accessibility of these sites for small molecules and water exchange. We have also computed the electric field exerted by GQ bases, which directs ions to bind to these locations. Our simulations have also revealed important details about ion competition in the ionic atmosphere around DNA GQs, as well as the extent to which ions must be dehydrated prior to entering the GQ core to become coordinated. The latter simulations reveal critical details about specificity of GQs for K+ over Na+ and Li+. Together, these simulations provide important biophysical insights into the properties of DNA GQs.

Ion interactions with DNA G-quadruplexes from Drude polarizable simulations: Hydration, thermodynamics, and competition

ACS Spring 2022

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